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Clinical Pharmacokinetics

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01-04-2007 | Original Research Article

Effect of Time, Injury, Age and Ethanol on Interpatient Variability in Valproic Acid Pharmacokinetics after Traumatic Brain Injury

Authors: Dr Gail D. Anderson, Nancy R. Temkin, Asaad B. Awan, H. Richard Winn

Published in: Clinical Pharmacokinetics | Issue 4/2007

Abstract

Background

Traumatic brain injury (TBI) results in an increase in hepatic metabolism. The increased metabolism is in significant contrast to a large body of in vitro and in vivo data demonstrating that activation of the host-defence response downregulates hepatic metabolism. Theoretically, this occurs because of activation of the pro-inflammatory cytokines tumour necrosis factor-α, interferon-γ, interleukin (IL)-1 and IL-6. As part of a large double-blind, placebo-controlled clinical trial evaluating the use of valproic acid for prophylaxis of post-traumatic seizures, we obtained extensive valproic acid concentration-time data. Valproic acid is a hepatically metabolised, low extraction-ratio drug. Therefore, unbound clearance (CL_u) is equal to intrinsic or metabolic clearance.

Objective

The objective of this study was to evaluate the time-dependent effects of TBI on the pharmacokinetics of total and unbound valproic acid with the goal of identifying patient factors that may predict changes in total clearance (CL) and CL_u. In addition, by determining the factors that influence the magnitude and time course of induction of hepatic metabolism and understanding their interaction with the host-defence mediators, we can further our insight into the mechanism(s) responsible for the changes in CL and CL_u.

Study Design

Valproic acid plasma concentration data were obtained from 158 TBI patients. Unbound valproic acid plasma concentrations were estimated using total valproic acid plasma and albumin concentrations following a Scatchard equation binding model previously developed in a subset of TBI patients. The effect of 13 patient factors on CL and CL_u was evaluated initially in a univariate analysis. The significant factors were then included in a multiple linear regression analysis by use of step-wise selection and forward selection procedures.

Results

CL and CL_u were significantly increased after TBI in a time-dependent manner. The average increase was >75% by weeks 2 and 3 post-injury. The magnitude of the induction of CL was increased with decreased albumin concentrations, in addition to the presence of ethanol on admission, increased severity of head injury, tube feeding and total parenteral nutrition (TPN). The magnitude of induction of CL_u was increased by older age, presence of ethanol on admission, increased severity of head injury, tube feeding, TPN, and if the patient had a post-injury neurosurgical procedure. The time to normalisation of CL_u was significantly longer in patients with head injury plus other injuries compared with those with head injury alone.

Conclusions

As has been reported with other drugs, TBI results in a significant increase in the metabolism of valproic acid. The patient factors identified in this study that resulted in an increase in the magnitude and time course of the induction of CL_u (ethanol, older age, presence of a neurosurgical procedure, severity of TBI and presence of multiple non-TBI injuries) have all been reported to cause a shift to the anti-inflammatory mediators IL-4 and IL-10. This suggests that the increase in hepatic metabolism after TBI may be due to the increased presence of antiinflammatory mediators in contrast to the inhibition effect of the pro-inflammatory mediators in non-TBI inflammation and infection.

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Title: Effect of Time, Injury, Age and Ethanol on Interpatient Variability in Valproic Acid Pharmacokinetics after Traumatic Brain Injury
Authors: Dr Gail D. Anderson
Nancy R. Temkin
Asaad B. Awan
H. Richard Winn
Publication date: 01-04-2007
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 4/2007
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200746040-00004

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Effect of Time, Injury, Age and Ethanol on Interpatient Variability in Valproic Acid Pharmacokinetics after Traumatic Brain Injury

Abstract

Background

Objective

Study Design

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objective

Study Design

Results

Conclusions

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